title: Studies on the mechanism of steroid 5 alpha-reductase inhibition by 3-carboxy A-ring aryl steroids.
abstract: The mechanism of interaction between two 3-carboxy A-ring aryl steroids, 17 beta-(N,N-diisopropylcarboxamide)-estra-1,3,5(10)-triene-3-carboxy lic acid (1) and 17 beta-(N-t-butylcarboxamide)-estra-1,3,5(10)-triene-3-carboxylic acid (2), with rat hepatic and human prostatic steroid 5 alpha-reductases has been investigated. Dead-end inhibition plots with 1 and 2 versus both substrates (testosterone and NADPH) were linear-uncompetitive using either enzyme, while double-inhibition analyses indicated cooperative binding to enzyme between NADP+ and 1 or 2. These results were interpreted within the ordered kinetic mechanism of steroid 5 alpha-reductase to result from the preferential association of 3-carboxy A-ring aryl steroids to the enzyme-NADP+ complex. The direct displacement by 2 of a radioligand known to associate to this same enzyme form provides further support for these conclusions.
authors.affiliation: Department of Medicinal Chemistry, Smith Kline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: M
authors.initials: M
authors.lastname: Brandt
authors.forename: A T
authors.initials: AT
authors.lastname: Greway
authors.forename: D A
authors.initials: DA
authors.lastname: Holt
authors.forename: B W
authors.initials: BW
authors.lastname: Metcalf
authors.forename: M A
authors.initials: MA
authors.lastname: Levy
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D004963:Estrenes / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008297:Male; D009249:NADP / Q000378:metabolism; D011467:Prostate / Q000201:enzymology; D051381:Rats; D013739:Testosterone / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D004963:Estrenes; C067104:17-(N,N-diisopropylcarboxamide)estra-1,3,5(10)-triene-3-carboxylic acid; C067105:17-(N-t-butylcarboxamide)estra-1,3,5(10)-triene-3-carboxylic acid; D013739:Testosterone; D009249:NADP; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase